期刊
CHEMISTRY & BIOLOGY
卷 16, 期 12, 页码 1278-1289出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2009.11.015
关键词
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资金
- American Cancer Society
- NCI [5RO1-CA124634]
- International Myeloma Foundation
- Friends of the Norris Cotton Cancer Center
- Netherlands Organization for Scientific Research
- Netherlands Genomics Initiative
Proteasomes degrade most proteins in mammalian cells and are established targets of anticancer drugs. All eukaryotic proteasomes have three types of active sites: chymotrypsin-like, trypsin-like, and caspase-like. Chymotrypsin-like sites are the most important in protein degradation and are the primary target of most proteasome inhibitors. The biological roles of trypsin-like and caspase-like sites and their potential as cotargets of antineoplastic agents are not well defined. Here we describe the development of site-specific inhibitors and active-site probes of chymotrypsin-like and caspase-like sites. Using these compounds, we show that cytotoxicity of proteasome inhibitors does not correlate with inhibition of chymotrypsin-like sites and that coinhibition of either trypsin-like and/or caspase-like sites is needed to achieve maximal cytotoxicity. Thus, caspase-like and trypsin-like sites must be considered as cotargets of anticancer drugs.
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